Treatment of cancer with larazotide derivatives in combination with immune checkpoint inhibitors

Abstract

The present invention provides compositions and methods for treating a patient having cancer, as well as methods for potentiating an immune checkpoint inhibitor therapy. The methods comprise administering larazotide or a derivative thereof such as (d)-larazotide to a subject in need, including subjects undergoing checkpoint inhibitor therapy, and subjects scheduled to undergo immune checkpoint inhibitor therapy.

What is claimed is: 
     
       1. A method for treating cancer in a patient undergoing an immune checkpoint inhibitor therapy targeting immune checkpoints selected from PD-1, PD-L1, and CTLA-4, the method comprising administering to the gastrointestinal tract of said patient an oral dosage composition comprising an amount effective to potentiate the immune checkpoint inhibitor therapy against the cancer of a peptide having the amino acid sequence of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, with the proviso that all non-glycine amino acid residues of SEQ ID NO: 1 are in (d) form. 
     
     
       2. The method of  claim 1 , wherein the immune checkpoint inhibitor is selected from ipilimumab, tremelimumab, pembrolizumab and nivolumab. 
     
     
       3. The method of  claim 1 , wherein the patient showed no response or only partial response to prior treatment with an immune checkpoint inhibitor therapy. 
     
     
       4. The method of  claim 3 , wherein the prior immune checkpoint inhibitor therapy was a PD-1 blockade therapy. 
     
     
       5. The method of  claim 1 , wherein the peptide is administered in a pharmaceutical composition that does not substantially release peptide in the stomach, and releases the peptide in the small intestine and/or large intestine. 
     
     
       6. The method of  claim 5 , wherein the peptide is released in one or more of the duodenum, jejunum, and the ileum. 
     
     
       7. The method of  claim 5 , wherein the peptide is released in the large intestine. 
     
     
       8. The method of  claim 7 , wherein the peptide is released in the colon. 
     
     
       9. The method of  claim 5 , wherein the peptide is administered in a sustained release formulation that releases peptide in the gastrointestinal tract for at least 2 hours. 
     
     
       10. The method of  claim 9 , wherein the sustained release formulation releases peptide in the gastrointestinal tract for at least 3 hours. 
     
     
       11. The method of  claim 1 , wherein the peptide is administered from 1 to 3 times per day. 
     
     
       12. The method of  claim 11 , wherein the peptide is administered throughout the immune checkpoint inhibitor therapy. 
     
     
       13. The method of  claim 12 , wherein the peptide is further administered after the immune checkpoint inhibitor therapy. 
     
     
       14. The method of  claim 11 , wherein the peptide is additionally administered for at least one week prior to initiation of the immune checkpoint inhibitor therapy. 
     
     
       15. The method of  claim 14 , wherein the peptide is administered throughout the duration of the immune checkpoint inhibitor therapy. 
     
     
       16. The method of  claim 15 , wherein the peptide is further administered after the checkpoint inhibitor therapy. 
     
     
       17. The method if  claim 1 , wherein the patient has primary cancer. 
     
     
       18. The method of  claim 1 , wherein the patient has metastatic cancer. 
     
     
       19. The method of  claim 18 , wherein the patient has metastatic melanoma. 
     
     
       20. The method of  claim 1 , wherein the patient has colorectal cancer. 
     
     
       21. The method of  claim 1 , wherein the patient has sarcoma or carcinoma. 
     
     
       22. The method of  claim 1 , wherein the patient has a hematological cancer. 
     
     
       23. The method of  claim 22 , wherein the patient has a leukemia, myeloma, or lymphoma.